This invention relates to diaryl naphthyl methanes and a process for preparation of said methane derivatives. The present invention particularly relates to a process or preparation of substituted secondary and tertiary amino alkoxy diaryl naphthyl methane derivatives, preparation of pharmaceutical composition containing such compounds as active ingredients and their use as contraceptives, in the treatment and prophylaxes of breast cancer, osteoporosis, hypercholesteremia, endometriosis, vasoconstriction, endometrial disorders and in estrogen replacement therapy (ERT).
Estrogen agonists as well as antagonists act through their interaction with estrogen receptor. This estrogen receptor protein has an active site where the ligand binds. It has been visualized as composed of two units, one having a shape complimentary to the structure of estradiol where estradiol finds a proper fit for producing estrogen agonistic activity. The second site provides binding of structural unit such as a substituted amino alkoxy aryl group thereby causing interference with the initiation of the hormonal activity as observed with estrogen antagonists. Based on this visualization, estrogen receptor model has been proposed easier. This present work utilizes the receptor model towards designing of novel estrogen antagonists.
The main object of the invention is to provide novel diarylnaphthyl methane compounds having structural Formula 1 and their derivatives, useful in the treatment of estrogen related diseases such as breast cancer, osteoporosis, hypercholesteremia, endometriosis, vasoconstriction, endometrial disorders and in estrogen replacement therapy (ERT).
Another object is to provide pharmaceutical compositions containing the novel diarylnaphthyl methane compounds having structural formula 1.
Yet another object is to provide methods for the preparation of novel diarylnapththyl methane compounds and their derivatives.
In accordance with the above and other objectives, the invention provides novel substituted diaryl naphthyl methane compounds having structural formula 1 and its derivatives, being a novel group of non-steroidal compounds and exhibiting estrogenic, antiestrogenic and contraceptive activities. The invention also provides methods for the preparation of the said novel diaryl naphthyl methane compounds and their derivatives. The invention also provides pharmaceutical compositions containing said novel diary naphthyl methane compounds and their derivatives.
Accordingly the invention provides novel diaryl naphthyl methane compounds having general formula 1 as shown herein below, 
wherein,
R1, R2, R3, R4, R5 represent H, OH, lower alkyl, lower alkoxy group having straight or branched chain radical containing 1-6 carbon atoms selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, n-amyl, n-hexyl, 2-ethyl butyl in case of lower alkyl and also as the alkyl residue constituting the lower alkoxy group, substituted alkoxy groups, epoxy alkoxy, alkyl/dialkyl amino alkoxy, cyclic alkyl amino alkoxy, the dotted indicate 1,2,3,4-tetrahydro naphthyl ring or 5,6,7,8-tetrahydronaphthyl ring, said compounds exhibiting estrogenic, antiestrogenic and contraceptive activities.
Substituted diaryl naphthyl methane derivatives, a novel group of non-steroidal compounds is showing promising estrogenic, antiestrogenic and contraceptive activities. The hormonal profile of such compounds is suitable for the treatment and prophylaxes of breast cancer, osteoporosis, hypercholesteremia, endometriosis, vasoconstriction, endometrial disorders and in estrogen replacement therapy.
The invention provides a novel substituted aminoalkoxy diaryl naphthyl methane derivatives thereof, represented by general formula 1 as shown hereinbelow: 
Wherein R1, R2, R3, R4, R5 are H, OH, lower alkyl, a substituted lower alkoxy group having a straight or branched chain radical containing 1-6 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, n-amyl, n-hexyl, 2-ethyl butyl in case of lower alkyl and also as the alkyl residue constituting the lower alkoxy group. Substituent on the alkyl chain of alkoxy radical can be H or OH, a substituted amino lower alkoxy group wherein the lower alkoxy substituent is as defined above, the substituent on the nitrogen atom is H, or a lower alkyl radical as defined above or constitutes a cyclic polymethylene system containing nitrogen atom, i.e. N(CH2)n wherein n=2-8. The naphthyl residue can be a substituted naphthyl, substituted 1,2,3,4-tetrahydronaphthyl or a substituted 5,6,7,8-tetrahydronaphthyl.
The compounds synthesized were tested for estrogenic, antiestrogenic activies in rats. A number of these compounds showed percent prevention of pregnancy at doses 10 mg per kg or below when administered orally to female albino rats on days 1-7 p.c. or on single day schedule.
The most preferred compounds, represented by formula 1 are given below:
1. (4-Methoxyphenyl)-(4-pyrrolidinoethoxyphenyl)-naphth-1-yl-methane HCl
2. (4-Methoxyphenyl)-(4-piperidinoethoxyphenyl)-naphth-1-yl-methane
3. (4-Methoxyphenyl)-(3-methyl4-piperidinoethoxyphenyl)-naphth-1-yl-methane
4. (4-Methoxyphenyl)-(4-pyrrolidinoethoxyphenyl)-1,2,3,4-tetrahydro-naphth-1-yl-methane
5. (4-Methoxyphenyl)-(4-pyrrolidinoethoxyphenyl)-5,6,7,8-tetrahydro-naphth-1-yl-methane HCl
6. (4-Methoxyphenyl)-(4-(2-hydroxy-3-cyclopropylamino)-propoxy)-phenyl-naphth-1-yl-methane
7. (4-Methoxyphenyl)-(4-(2-hydroxy-3-n-butylamino-propoxy)phenyl)-1,2,3,4-tetrahydronaphth-1-yl-methane
The most preferred compounds belonging to the class of diary naphthyl methanes represented by formula Ia are given below: 
1. (4-Methoxyphenyl)-(4-pyrrolidinoethoxyphenyl)-naphth1-yl-methane HCl
2. (4-Methoxyphenyl)-(4-piperidinoethoxyphenyl)-naphth-1-yl-methane
3. (4-Methoxyphenyl)-(3-methyl-piperidinoethoxyphenyl)-naphth-1-yl-methane
The invention includes within the scope partially reduced substituted naphthalene residue to provide derivatives of substituted diaryl 1,2,3,4-tetrahydro naphthyl methane represented by the general formula Ib wherein R1, R2, R3, R4, R5, have the meaning as stated above. 
Preferred compounds belonging to Ib are:
1. (4-Methoxyphenyl)-(4-piperidinoethoxyphenyl)-1,2,3,4-tetrahydronapth-1-yl-methane.
2. (4-methoxyphenyl)-(3-methyl-4-piperidinoethoxyphenyl)-1,2,3,4-tetrahydronaphth-1-yl-methane. 3. (4-Methoxyphenyl)-(4-(2-hydroxy-3-n-dibutylaminopropoxy)phenyl-1,2,3,4-tetrahydronaphth-1-yl-methane.
In yet another modification included within the scope are the partially reduced naphthalene residue containing derivatives of substituted diaryl 5,6,7,8-tetrahydro naphthyl methane represented by the general formula Ic. 
wherein R1, R2, R3, R4, R5 have the meanings as stated above.
Preferred compounds of Ic are:
1. (4-Methoxyphenyl)-(4-pyrrolidinoethoxyphenyl)-5,6,7,8-tetrahydronaphth-1-yl-methane hydrochloride.
2. (4-Methoxyphenyl)-(4-N,N-diethylamino-ethoxyphenyl)-5,6,7,8-tetrahydro-naphth-1-yl-methane.
The preparation of compounds shown in formula 1, wherein R1, R2, R3, R4, R5 are as defined above is described hereinbelow. The process comprises the steps of conducting Friedel-Crafts reaction of substituted xcex1-naphthoic acid with the substituted phenol in the presence of Lewis acid to give a naphthophenone derivative which is reduced by a metal hydride in a protic solvent to the corresponding alcohol which is subjected to a second Friedel-Crafts reaction with a phenol derivative in the presence of a Lewis acid under low temperature to produce compound of formula 1 wherein one of the substituent R1, R2, R3, R4, R5 is a hydroxy group which is reacted with a tertiary amino alkyl chloride to produce corresponding tertiary amino alkoxy compound or alternatively treated with epichlorohydrin under basic condition either neat or in organic solvent such as acetone, DMSO to produce corresponding 2,3-epoxy-propyloxy derivatives which on treatment with an amine produce hydroxy substituted corresponding secondary amino alkoxy derivatives.
Typical composition includes a compound of formula 1 or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluents or be diluted or be diluted by a carrier or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. In making the composition, conventional techniques for the preparation of pharmaceutical composition may be used for example the active compound will usually be mixed with a carrier, or diluted by a carrier, enclosed within a container, which may be in the form of an ampoule, capsule, sachet paper or other container. When the carrier serves as a diluent, it may be solid, semi-solid or liquid material which act as a vehicle, excipient, or medium of the active compound. The active compound can be adsorbed on a granular solid. Some examples of suitable carriers are water, salt solution, alcohol, polyethyleneglycol, polyhydroxyethoxylated castor oil, gelatine, lactose, amylase, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidene. The formulation may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents. The formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to %he patient by employing procedures well known in the art.
The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compounds dissolved in polyhydroxylated castor oil.
Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
The compound according to this invention may be suitable for administration to an animal. Such animals include both domestic animals, for example livestock, laboratory animals, and household pets, and non-domestic animals such as wildlife. More preferably, the animal is a vertebrate. Most preferably a compound according to this invention shall be administrated to a mammal. It is especially preferred that the animal is a domestic animal or a human. The most preferred mammal is a human. For such purposes, a compound of this invention may be administrated as a feed additive or in bulk form.
The preparation of the novel compounds and its derivatives are described in the following non-imitative examples.
Novel diaryl naphthyl methanes of formula I have been prepared 
Accordingly the present invention provides novel diaryl naphthyl methanes and a process for the preparation of said methane compounds of general formula I useful in the treatment of estrogen related disease or syndrome wherein R1, R2, R3, R4, R5 are (H, OH, lower alkyl, lower alkoxy group having straight or branched chain radical containing 1-6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, n-amyl, n-hexyl, 2-ethyl butyl in case of lower alkyl and also as the alkyl residue constituting the lower alkoxy group, substituted alkoxy groups, epoxy alkoxy, alkyl/dialkyl amino alkoxy, cyclic alkyl aminoalkoxy, hydroxy substituted alkyl/dialkyl/cyclic alkyl aminoalkoxy, the dotted lines indicate 1,2,3,4-tetrahydro naphthyl ring or 5,6,7,8-tetrahydronaphthyl ring, which comprises (i) reacting a compound of formula II wherein 
R1, R2 and R3 is H, OH, alkyl or alkoxy as stated above with phenolic compound under the conventional. Friedel Crafts reaction conditions to produce the compound of Formula I wherein R1, R2, R3, R4 is H, OH, alkyl or alkoxy as stated above and R5 is OH dotted lines indicate the presence of double bonds (ii) optionally subjecting the compound of formula I as obtained above in step (I) to the conventional hydrogenation conditions to give the tetrahydronaphthyl compound of formula I wherein dotted lines in one ring of the naphthyl group show the presence of double bonds; (iii) reacting compound of formula I wherein R1, R2, R3, R4 are as stated above in step (I), R5 is OH with an alkylating agent in the presence of a base at a temperature in the range 300 to 120xc2x0 C. for a period in the range of 1-12 hrs and recovering the alkylated product of formula I wherein R5 is alkoxy, epoxy alkoxy, alkyl or dialkyl amino alkoxy, cyclic alkyl aminoalkoxy, cyclic alkyl amino alkoxy, R1, R2, R3 and R4 are as stated above in step (I), (iv) reacting compound of formula I wherein R5 is epoxy alkoxy with an amine at a temperature in the range of 30 to 120xc2x0 C. for a period in the range of 1 to 12 hr and recovering the compound of formula I wherein R1, R2, R3, R4 are as stated above in step (I) and R5 is hydroxy substituted alkyl/dialkyl/cyclic alkyl amino alkoxy group, converting the amino compounds of formula I to their salts by known methods.
Novel compounds of general formula 1
wherein the preferred compounds are represented below
1. (4-Methoxyphenyl)-(4-pyrrolidinoethoxyphen-yl-methane HCl
2. (4-Methoxyphenyl)-(4-piperidinoethoxyphenyl)-naphth-1-yl-methane
3. (4-Methoxyphenyl)-(3-methyl-4-piperidinoethoxyphenyl-naphth-1-yl-methane
4. (4-Methoxyphenyl)-(4-pyrrolidinoethoxyphenyl)-1,2,3,4-tetrahydro-naphth-1-yl-methane
5. (4-Methoxyphenyl)-(4-pyrrolidinoethoxyphenyl)-5,6,7,8-tetrahydro-naphth-1-yl-methane HCl
6. (4-Methoxyphenyl)-(4-2-hydroxy-3-cyclopropylamino)-propoxy)-phenyl-naphth-1-yl-methane
7. (4-Methoxyphenyl)-(4-(2-hydroxy-3-n-butylamino-propoxy)phenyl)-1,2,3,4-tetrahydronaphth-1-yl-methane
In an embodiment of the present invention, the catalyst used for Friedel-Crafts reaction is such as AlCl3, SnCl4, or (CH3)3SiCl.
In another embodiment of the present invention, the solvent used for Friedel-Crafts reaction is hydrocarbon solvents such as benzene, toluene, hexane or pentane.
In another embodiment of the present invention, the reaction is effected at a temperature in the range of xe2x88x9220xc2x0 C. to 100xc2x0 C. for a period in the range of 1 to 10 hr.
In still another embodiment of the present invention, the catalyst used for hydrogenation is such as Raney Ni, Pd/C, or Pt2O.
In yet another embodiment of the present invention, the hydrogenation is effected at a pressure in the range of 30 to 60 psi at a temperature in the range of 25xc2x0 to 60xc2x0 C. in presence of solvent such as methanol, ethanol, or THF.
In yet another embodiment of the present invention the alkylation is carried out neat or in a non polar solvent, such as acetone, DMSO, in the presence of a base such as K2CO3, NaOH, KOH, or organic base.
In yet another embodiment of the present invention, the amine used is such as primary or secondary amine containing carbon atoms 2 to 6.
In yet another embodiment of the present invention, the reaction is step (iv) in carried out neat (without solvent) or in presence of polar solvent such as methanol, ethanol, or THF.
In yet another embodiment of the present invention, the salts of formula 1 include hydrochloride, tartrates, citrate, or succinate.
In yet, another embodiment of the present invention, the pharmaceutical composition comprises a compound of formula 1 in an appropriate amount in admixture with a pharmaceutical carrier or a diluent.
In yet another embodiment of the present invention, the compound is used for the prevention and treatment of estrogen related disease or syndromes.